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Atherosclerosis
Focal plaques within the intima containing cholesteroland cholesterol esters (CE)
Affects large and medium sized arteries
Causes coronary heart diseases (CHD)
Hypercholesterolemia high serum cholesterol level
Elevated LDL and triglyceridesassociated with increase risk
Serum HDL levels inversely related to risk
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Pathogenesis
Chronic inflammatory response of the vascularwall to endothelial injury or dysfunction
Elevated plasma LDL levels causing the depositof LDL in the subendothelium of blood vessels
Oxidation of transmigrated LDL Activation of endothelial cells
Recruitment of monocytes/macrophages whichingest oxLDL through scavenger receptors
Formation of foam cells fatty streaks Proliferation of smooth muscle cells
Deposition of extracellular matrix proteins
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Monocyte Recruitment
intima
lumen LDL
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Lipid Core
lumen
neointima
Formation of Atherosclerotic Plaques
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Plaque Rupture and Thrombosis
Lipid Core
Tissue Factor Platelet Aggregation
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Cholesterol and Triglyceride Metabolism
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Exogenous Pathway
Route of uptake of dietary lipids.
Chylomicrons (CM)
complexes of TG, CE and apoproteins
Chylomicron remnants
CM after removal of most TG CM are degraded by lipoprotein lipase on endothelial
cells of adipose tissue and muscle. After removal of TGfor storage, CM remnants are transported to the liver.
Results: Dietary TG is stored in adipose tissue andmuscle. Cholesterol is stored in liver or excreted into thebile as cholesterol or bile acid.
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Cholesterol and Triglyceride Metabolism
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Endogenous Pathway
Route for distribution of CE from liver to target cells
VLDL secreted by the liver to plasma and transportedto adipose tissue and muscle where lipoprotein lipaseextracted TG. The remnant IDL is either taken up by theliver or circulates until the remaining TG is removed,forming LDL particles which are rich in cholesterol.
LDL is cleared from plasma by LDL receptor-mediatedendocytosis.
Results: 1) Transfer of TG from liver to target cells via
VLDL; 2) Transfer of CE from liver to target cells viaLDL; 3) Feedback regulation of cholesterol homeostasisby LDL receptor expression; 4) Creation of a steadystate LDL-CE reserve in plasma.
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Cholesterol and Triglyceride Metabolism
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Reverse Transport of Cholesterol
Route for cholesterol recovery
As cell dies and the cell membrane turnover, freecholesterol is released into the plasma. It is immediatelyabsorbed onto HDL particles, esterified with a long chainfatty acid by lecithin:cholesterol acyltransferase (LCAT),
and transferred to VLDL or IDL by a cholesteryl estertransfer protein (CETP) in plasma. Eventually, it is takenup by the liver as IDL or LDL.
Results: Recovery of cholesterol from cell membranesand reincorporation into LDL pool or return to liver.
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Cholesterol and Triglyceride Metabolism
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De NovoCholesterol Biosynthesis
Liver synthesizes 2/3 of cholesterol made by the body.
The rate limiting enzyme is 3-hydroxyl 3-methyl glutaryl(HMG)-CoA reductase.
Results: Provide feedback regulation by cholesterol
concentrations in cells.
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Cholesterol Excretion byEnterohepatic Circulation
Bile acids are synthesized from cholesterol in the liver,released into the intestine and reabsorbed in the jejunumand ileum.
Results: Conversion of liver cholesterol to bile acids forrecycle.
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Genetic Defects of Lipid Metabolism
Monogenic
Familial hypercholesterolemia
(homozygous or heterozygous)
defect: inactive LDL receptor
Familial lipoprotein lipase deficiencydefect: inactive lipoprotein lipase
Familial combined hyperlipidemia
defect: unknown
Polygenic/multifactorial commonly encountered
Hypercholesterolemia
Hypertriglyceridemia
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Therapeutic Strategy
A. Identify patients at risk1. Routine screening of serum cholesterol
2. Assessment of contributing risk factors
B. Non-pharmacologic therapy
1. Diet modification
2. Lifestyle modification
C. Pharmacologic therapy
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Classification ofPlasma Cholesterol Concentrations
Total cholesterol
(mg/dl)
Classification
< 200 Desirable
200 - 239 Borderline
> 240 High
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Lovastatin aka statins(HMG-CoA reductase inhibitors)
Action: competitively inhibits HMG-CoA reductase, thekey enzyme for de novocholesterol biosynthesis.
Results: 1) cells express more LDL receptors; 2)
decreased serum LDL levels; 3) suppresses productionof VLDL in liver; 4) increased HDL levels; 5) increasedHDL/LDL ratio.
Advantages: specific; effective; well-tolerated.
Disadvantages: hepatotoxicity; myopathy; mostexpensive; contradicted in pregnant and nursing women.
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Bile acid sequestrants(colestipol, cholestyramine, colesevelam)
Taken orally, not absorbed from the intestine.
Action: Anion exchange resins which bind negativelycharged bile acids in the small intestine.
Results: 1) increased conversion of cholesterol to bileacid in hepatocytes; 2) increased synthesis ofcholesterol and LDL receptors in hepatocytes; 3)decreased serum LDL and cholesterol levels.
Advantages: clinically safe; effective.
Disadvantages: unpleasant GI effects; interference withGI drug absorption (e.g., coumarin); may exacerbatehypertriglyceridemia (unknown mechanism).
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Ezetimibe
Action: inhibits dietary cholesterol uptake by jejunalenterocytes by binding to a key mediator of cholesterolabsorption Neimann-Pick C1-Like1 (NPC1L1).
Results: 1) reduction of cholesterol incorporation intochylomicrons and delivery to hepatocytes; 2) increased
synthesis of cholesterol and LDL receptors in hepatocytes;3) decreased serum LDL and cholesterol levels.
Advantages: clinically safe; effective; used asmonotherapy in statin-intolerant patients; also used incombination with statins in statin-tolerant patients for
further reduction of serum LDL and cholesterol. Disadvantages: no effect on TG absorption; a new class of
anti-atherosclerotic drug long term effect not known.
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Niacin (nicotinic acid)
Action: Acts through a Gi-coupled GPCR to decreasecAMP levels. Inhibits hormone-sensitive lipase involved inlipolysis in adipose tissue and decreases free fatty acid(FFA) transfer to the liver for synthesis of triglycerides.
Results: 1) decreased production and release of VLDL by
liver; 2) decreased serum levels of VLDL as well as LDLand TG; 3) reduced clearance of HDL or increased serumlevel of HDL; 4) increased HDL/LDL ratio.
Advantages: long clinical experience; effective; leastexpensive.
Disadvantages: evokes flushing, itchiness, dyspepsia andGI discomfort, contraindicated for diabetic patients andpregnant women; adverse effects in hepatic diseases andreactivation of gout.
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Fibrates (prototype: clofibrateUS: gemfibrozil; Europe: fenofibrate)
Action: acts through peroxisome proliferator activatedreceptors (PPARs) to stimulate gene transcription oflipoprotein lipase; increases the clearance of VLDL andreduce plasma TG levels; decreases VLDL synthesis andlowers LDL levels moderately; increases plasma HDL byincreased synthesis and/or decreased clearance.
Results: decreased serum TG and cholesterol; increasedHDL/LDL ratio.
Advantages: recent clinical data support safety and
efficacy; well-tolerated, potential anti-thrombotic effect. Disadvantages: more effective in reducing TG than LDL;
increased LDL levels in some patients; displacesanticoagulant from albumin; contraindicated in patientswith renal failure. Clofibrate has toxic effect.
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CETP Inhibitors (Torcetrapib)
Action: Inhibits the transfer of cholesterol ester from HDLto VLDL.
Results: 1) increased serum level of HDL; 2) by itself, noeffect on LDL levels; 3) use in combination of statins tolower LDL with further increase in HDL.
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Combined Drug Therapy
Advantages: Synergistic approaches utilizes
complementary mechanisms of drug actions; reduceseffective doses of single drug to prevent side effects.
Hypercholesterol without hypertriglycerides:
Bile acid sequestrant plus lovastatin
Ezetimibe plus lovastatin
Bile acid sequestrant plus lovastatin plus ezetimibe
Bile acid sequestrant plus nicotinic acid
Bile acid sequestrant plus gemfibrozil (less common)
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Hypercholesterol with hypertriglycerides:
Nicotinic acid plus lovastatin
Lovastatin plus gemfibrozil
Nicotinic acid plus lovastatin plus bile acid sequestrant
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Probucol(lipophilic antioxidant)
Action: Taken up by LDL particles and endothelial cells.Inhibits oxidation of LDL and prevents ingestion bymacrophage foam cells. Decreases HDL production.
Results: 1) decreases atherosclerotic plaque formation;
2) small reduction in serum LDL-cholesterol; 3) greaterreduction of serum HDL-cholesterol.
Advantages: may be used in combination therapy withother drugs that lower serum LDL-cholesterol.
Disadvantages: not effective in single drug therapy; nolong term clinical data.
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